During breathing, the respiratory system transports breathing gases to the lungs, carries out a gas exchange in which oxygen (O.sub.2) is supplied to the blood and carbon dioxide (CO.sub.2) is removed from the blood, and returns the breathing gases to the source. Typically, the breathing gases are those found in air and are taken from, and returned to, the atmosphere through the mouth and nose of a subject by his/her natural breathing action. However, a mechanical ventilator may be employed to assist or supplant the natural breathing action by supplying/receiving breathing gases through a mask, endotracheal tube, or tracheotomy tube.
The amount of breathing gases breathed in and out of the lungs in normal breathing is termed the tidal volume (V.sub.T). This is typically 400-700 milliliters (ml) per breath. The lungs also have a residual volume beyond that participating in the normal breathing action. This volume is termed the functional residual capacity (FRC) and is the volume of breathing gases remaining in the lungs at the end of a normal exhalation or expiration. For a typical subject, the functional residual capacity may be 700-3500 ml.
The foregoing and other lung volumes are formed in the alveoli and breathing passages of the lung. The alveoli are small air sacs at the end of the respiratory airway, each of which is served by a pulmonary capillary. The major function of the alveoli is to carry out the gas exchange between breathing gases supplied by the respiratory system and the blood in the circulatory system.
For effective gas exchange between the breathing gas in the lungs and the blood in the capillaries, there must be adequate amounts of both ventilation (alveolar breathing gases) and perfusion (capillary blood flow). If either is impaired, gas exchange will suffer. For example, where there is ventilation without perfusion, a unit of "dead space" exists in the lungs and gas exchange is lessened or prevented. An example of this is the presence of a pulmonary embolus that prevents blood flow through a pulmonary capillary. Similarly, where there is no ventilation of a portion of the lung but perfusion is present, a "shunt" is said to exist and gas exchange is also lessened or prevented. This may occur with a collapse of alveoli in the lungs (atelectasis). The foregoing represent extreme cases. In most situations, any losses in gas exchange efficiency are due to reductions, rather than blockage, in ventilation or perfusion.
A convenient way to express the effectiveness of gas exchange occurring in a subject's lungs is by the ratio of the amount of air (V) respired in the lungs (ventilation) to the blood flow (Q) occurring in the lungs (perfusion). This ratio is termed the ventilation/perfusion or "V/Q" ratio. A low ventilation/perfusion ratio (shunt-like condition) or a high ventilation/perfusion ratio (dead space-like condition) both result in lessened gas exchange and lower oxygen levels in the blood. Knowing the V/Q ratio is useful in preventing hypoxia in the subject and in diagnosing conditions, such as, pulmonary embolism, pulmonary infarction, emphysema, fibrosis, bronchiectasis, as well as in the preoperative assessment of candidates for surgical resection of, for example, a thoracic malignancy.
A ventilation/perfusion ratio can be obtained from a subject's tidal volume of breathing gases and pulmonary blood flow. However, the lungs contain millions of alveoli, each of which have individual gas exchange characteristics due to anatomy, disease, aging, or for other reasons. An overall V/Q ratio obtained from tidal volume and pulmonary blood flow is thus a rather gross measure of the complexity and range in efficacy of the gas exchange actually occurring in a subject's lungs. V/Q data that provides information regarding the range of V/Q ratios found in the lungs and the relative presence or "distribution" of the various V/Q ratios would more precisely reflect the health of the lungs and be much more useful for diagnostic and other purposes. Using a simple example, such data might show that a seemingly normal overall V/Q ratio actually consists of a component of normal V/Q ratios, a portion of high V/Q ratios and a portion of low V/Q ratios. The normal overall V/Q ratio would indicate that adequate oxygenation is occurring whereas knowledge of the distribution of the various V/Q ratios might call this into question.
One way to obtain information regarding the V/Q ratio is to inject a radioactive dye intravenously, and allow it to be carried into the pulmonary vasculature where decreased blood flow, if present, can be seen by x-ray film or a radioactivity detector. For ventilation, radioactive gas is inhaled to similarly produce an image of areas where ventilation is or is not occurring. While this technique is straightforward and simple, it suffers from inaccuracies and it is difficult to determine differing V/Q ratios and the distribution of the range of V/Q ratios.
A more sophisticated technique for determining ventilation/perfusion ratios employs a plurality of different gases, the solubilities of which, in blood, range from very low, for example, sulfur hexafluoride (SF.sub.6) to very high, such as acetone. This technique is called the multiple inert gas elimination technique (MIGET). The gases are infused at a constant rate into a peripheral vein of a subject located, for example, in the arm. With the gases absorbed and circulating in the blood stream of the subject, some amount of each gas in the blood undergoes gas exchange in the alveoli of the lungs and is eliminated from the body upon expiration. The relationship between the amount of a particular gas eliminated and the amount of that gas that remains in the blood is governed by the ventilation/perfusion ratio and the solubility of the gas in the blood.
The use of gases with different solubilities permits the range of V/Q ratios and their distribution to be determined. The manner in which this is accomplished is explained in a simplified fashion, as follows. For simplicity, it is assumed that the ventilation is generally uniform throughout the lungs, i.e. is homogeneous, whereas perfusion is not uniform throughout the lungs, i.e. some alveoli have greater perfusion than others. For a gas that is highly soluble in the blood, only a small portion will be exchanged to the alveolar breathing gases because of the tendency for the gas to remain in the blood. The exchange that does occur will take place in those alveoli which have high perfusion. Thus the presence of a high blood solubility gas in the respiratory and circulatory systems of the subject, in effect, divides the alveoli of the lungs into two categories. The first category is those that have high perfusion. The second category is those that do not have high perfusion. This, in turn, establishes two V/Q ratio categories: first, alveoli having a lower V/Q ratio; and second, alveoli that do not have the lower V/Q ratio. The amounts of the gas found in the expired air of the subject come from alveoli of the first category (high perfusion).
For a gas that has a low solubility in the blood, a large portion of the gas will tend to be exchanged to the alveolar breathing gases and discharged on expiration. The exception will be alveoli having low perfusion. A low blood solubility gas will also divide the lungs into two categories: those with low perfusion; and those not having low perfusion; each with different V/Q ratios.
The same phenomenon occurs for each gas of differing solubility with the division into categories occurring at a different V/Q ratio. By subjecting the combined blood gas-expiration gas data for all gases to appropriate mathematical analysis, the range of V/Q ratios in a subject's lungs and the distribution of the V/Q ratios can be determined.
Because of the mathematical treatment used to obtain such quantitative results and to model the lungs, the categorizations of lung characteristics resulting from the mathematical treatment are often expressed as "compartments." However, it is to be understood that such compartmental descriptions are analytical concepts that do not necessarily have a direct correlation to anatomical portions of the lungs, such as lobes.
Due to its ability to obtain the information described above, the MIGET has received widespread acceptance as a tool for diagnosing the condition of the lungs and efficacy of gas exchange therein. The MIGET is further described in Wagner P. D., Salzman H. A., West J. B., Measurement of continuous distribution of ventilation-perfusion ratios: theory, J Appl Physiol 1974; 36:588-99 and Roca J. and Wagner P. D., Principles and information content of the multiple inert gas elimination technique, Thorax 1993; 49:815-824.
However, while useful, the multiple inert gas elimination technique is very laborious and invasive. The technique requires infusion of the gas mixture into a vein of one arm of the subject, collection of arterial and venous samples from the other arm of the subject, and measurement of the concentration of each of the gases in the expired breathing gases of the subject. It takes a considerable period of time (40 mins.) for physiological equilibrium to be reached, after which the blood samples and expired concentrations can be taken for use in determining the V/Q ratio information.
Further, because the MIGET is carried out under steady state conditions, there are certain lung characteristics that are not amenable to determination by this technique. For example, another quantification of lung physiology that is useful for diagnostic purposes is ventilation per unit of alveolar gas volume and particularly the distribution of this quantification. This ratio is the relationship of the tidal volume (V.sub.T) to the functional residual capacity (FRC) of the lungs. When described on the basis of compartments (i), it is expressed as V.sub.ti /V.sub.ai, functional residual capacity being the sum of the alveolar volumes (V.sub.ai), i.e. FRC=.SIGMA..sub.i V.sub.ai. The distribution of this quantification indicates how homogeneously the ventilation is distributed in the lungs. For adequate oxygenation, it is desirable to have homogeneous distribution of ventilation in the lung volume. Knowing the V.sub.t /V.sub.a distribution for a given subject is a useful addition to other data concerning the lungs. For example, if the V.sub.t /V.sub.a data is normal but the V/Q data is abnormal, this would tend to indicate that a lung problem lies with perfusion (Q), not ventilation, characteristics. If both distributions are abnormal, the problem may lie with ventilation.
However, because of the steady-state nature of the multiple inert gas elimination technique, it does not give information regarding the ventilation per unit of gas volume (V.sub.t /V.sub.a) and its distribution characteristics. Depending on particular diagnostic requirements, this can be a significant limitation.
Other diagnostic information regarding the lung that may be usefull is pulmonary tissue volume and the amount of water (edema) in the lungs. However, it is not possible to determine pulmonary tissue volume or the amount of lung water with the MIGET because, in steady state, the lung tissue and lung water act only as static storages of gas with zero net transfer of gas. With zero net gas transfer, no measurements can be made that would enable these quantities to be determined.
Techniques do exist for determining these quantities using a blood soluble inert gas and an insoluble inert gas. Such techniques can also be used to measure pulmonary blood flow. See Overland E. S. et al., Measurement of pulmonary tissue volume and blood flowing in persons with normal and edematous lungs. J Appln Physiol 1981; 51(6): 1375-1383; Sackner M A, Measurement of cardiac output by alveolar gas exchange. In: Fishman AP et al., eds. Handbook of Physiology, Section 3: Volume IV; Bethesda: American Physiological Society, 1987; 233-255; and Kennedy R R and Baker A B, Solubility characteristics of the ideal agent for measurement of cardiac output by soluble gas uptake methods, Br. J. Anaesth. 1993; 71: 398-402.
In these other techniques for determining lung tissue volume, lung water, and pulmonary blood flow, the lungs are assumed to be homogeneous in nature, i.e., consist of one compartment. However, this means that for subjects with inhomogeneities in either the ventilation/perfusion ratios (V.sub.i /Q).sub.i distribution or the ventilation/volume ratios (V.sub.t /V.sub.a).sub.i distribution, the measurements will give false results.